Inside Health

Familiar Blood Pressure Drug Finds an Array of Novel Uses

By MARY DUENWALD

Published: June 25, 2002

For 20 years, doctors have used ACE inhibitors to control blood pressure in heart patients. But now it is becoming increasingly clear that these drugs -- with names like ramipril and capoten -- can do much more than merely relax the arteries, allowing blood to flow more freely.

Results of the newest studies of ACE (angiotensin converting enzyme) inhibitors, and of newer drugs known as A.R.B.'s (angiotensin receptor blockers), which work in a similar way -- have shown that they can prevent heart attack, stroke and even new cases of diabetes in a variety of patients. ACE inhibitors appear also to be able to slow muscle decline in the elderly. The drugs' ability to provide all these benefits, doctors say, extends beyond their effect on blood pressure.

It is a story reminiscent of the history of aspirin, a drug that began life as a mere pain reliever and turned out to be able to help prevent heart attacks and strokes, said Dr. Salim Yusuf, director of cardiology at McMaster University in Hamilton, Ontario.

''We're at the same place with ACE inhibitors that we were with aspirin 10 to 15 years ago,'' he said. ''We're finding that blood pressure lowering is only part of the story. We're finding that they have many mechanisms of action that are protective against cardiovascular disease.''

This new understanding means, first of all, that the drugs will be coming into wider use. The American Heart Association has recently urged physicians to consider using ACE inhibitors to treat a wider population of heart attack survivors, diabetics and patients with other cardiovascular risk factors.

But the discovery that these drugs have such diverse benefits is also enhancing understanding of heart disease and diabetes. Scientists are beginning to see how one of the body's own proteins, angiotensin, the hormone that both ACE inhibitors and A.R.B.'s interfere with, can play a significant role in promoting chronic diseases. It is a story in which a substance apparently designed by natural selection to help people survive in the short term turns out to do damage over the course of many years to the arteries, the heart and other organs.

Angiotensin is a part of a cascade of proteins that the body produces when it senses that blood pressure is too low -- as it would in the case of a severely bleeding injury or extreme diarrhea. It constricts the blood vessels, preventing the loss of too much blood and fluid. It is an important mechanism, but one that is possible to live without in modern times, when people no longer stand a high risk of such injury.

''When people were running from saber-toothed tigers and had no ability to stitch up a cut, angiotensin was very important,'' said Dr. Richard B. Devereux, professor of medicine at Weill Medical College of Cornell University. ''If you're safe from such things, then it seems like you can pretty well do away with angiotensin, in adults, and not do any harm.''

Doctors are finding that the damage angiotensin itself can do over the long term is considerable. In addition to raising blood pressure, it promotes the buildup of plaques in the arteries, helps instigate the rupture of those plaques, encourages blood clotting and increases the degree to which the heart muscle enlarges after a heart attack. The mechanisms of its action are unclear and are the focus of studies in laboratory animals. But some scientists suspect that angiotensin may work some of its damage by causing inflammation.

''There is good evidence that angiotensin not only causes inflammation, but it also increases the expression of other agents, such as interleukin-6, that cause inflammation,'' said Dr. Peter Libby, chief of cardiovascular medicine at Brigham and Women's Hospital in Boston.

ACE inhibitors block the enzyme that creates angiotensin II, the most active form of the substance. And A.R.B.'s -- drugs like losartan and valsartan -- prevent angiotensin from attaching to receptors on cell surfaces. The receptor blockers are newer, having come on the market in 1995. They are preferable, doctors say, for the 15 to 30 percent of patients who develop side effects from ACE inhibitors, mainly a persistent and sometimes intolerable cough. But ACE inhibitors, because they are older, are more familiar and can be less expensive.

Almost from the earliest use of ACE inhibitors, certain scientists suspected they could do more than relax the blood vessels. Studies in laboratory rats and humans, in the 1970's and 1980's, showed that the drugs could also reduce the heart muscle enlargement that typically happens after a heart attack. ACE inhibitors, these studies showed, reduced the degree of heart remodeling, and this decreased the risk of heart failure and prolonged survival time.

''Fewer people died,'' Dr. Marc A. Pfeffer, co-chief of medicine at the Veterans Administration Boston Health Care System, said about a trial of ACE inhibitors in heart attack survivors, which he directed a decade ago. ''But also, fewer had second heart attacks. That was surprising and very exciting.''